[go: up one dir, main page]

EP1752443A1 - Nouvelle forme cristalline V de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent - Google Patents

Nouvelle forme cristalline V de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent Download PDF

Info

Publication number
EP1752443A1
EP1752443A1 EP06291251A EP06291251A EP1752443A1 EP 1752443 A1 EP1752443 A1 EP 1752443A1 EP 06291251 A EP06291251 A EP 06291251A EP 06291251 A EP06291251 A EP 06291251A EP 1752443 A1 EP1752443 A1 EP 1752443A1
Authority
EP
European Patent Office
Prior art keywords
crystalline form
agomelatine
disorders
formula
pharmaceutical compositions
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06291251A
Other languages
German (de)
English (en)
Other versions
EP1752443B1 (fr
Inventor
Gérard Coquerel
Julie Linol
Jean-Claude Souvie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoires Servier SAS
Original Assignee
Laboratoires Servier SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36581629&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1752443(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Priority to MEP-2012-327A priority Critical patent/ME02026B/fr
Priority to EP10011469A priority patent/EP2277857A3/fr
Priority to SI200631396T priority patent/SI1752443T1/sl
Priority to PL06291251T priority patent/PL1752443T3/pl
Publication of EP1752443A1 publication Critical patent/EP1752443A1/fr
Application granted granted Critical
Publication of EP1752443B1 publication Critical patent/EP1752443B1/fr
Priority to CY20121100635T priority patent/CY1113011T1/el
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel crystalline form V of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide of formula (I): its preparation process as well as the pharmaceutical compositions containing it.
  • the patent EP 0 447 285 describes the eight-step access to agomelatine from 7-methoxy-1-tetralone. However, this document does not specify the conditions for obtaining agomelatine in a form having these characteristics in a reproducible manner.
  • the Applicant has now developed a method for obtaining agomelatine in a well-defined crystalline form, perfectly reproducible and thus having interesting characteristics of dissolution and ease of formulation.
  • the present invention relates to the crystalline form V of the compound of formula (I), characterized by the following X-ray powder diffraction pattern, measured on a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-reticular distance d, Bragg angle 2 theta, and relative intensity (expressed as a percentage of the most intense line): 2-Theta (°) d ( ⁇ ) Intensity exp. exp.
  • the invention also extends to the process for preparing the crystalline form V of the compound of formula (I), characterized in that the agomelatine is subjected to mechanical grinding said "high energy".
  • the crystallization process according to the invention it is possible to use the compound of formula (I) obtained by any process.
  • the invention also extends to another process for the preparation of the crystalline form V of the compound of formula (I), characterized in that the agomelatine is heated until complete melting and then it is placed at room temperature and at the same time, a very small amount of the crystalline form V of the freshly prepared compound of formula (I) is added and then allowed to cool to complete crystallization.
  • the agomelatine will be melted at 110 ° C.
  • the amount of crystalline form V added in this second crystallization process according to the invention will preferably be between 1/100 and 1/50 of the weight of agomelatine.
  • this second crystallization process according to the invention it is possible to use the compound of formula (I) obtained by any process.
  • the pharmacological study of the form V thus obtained showed an important activity on the central nervous system as well as on the microcirculation which makes it possible to establish its utility in the treatment of the stress, the sleep disorders, the anxiety, the major depression, seasonal depression, cardiovascular diseases, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity , insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory, Alzheimer's disease, as well as in disorders of the cerebral circulation.
  • the form V of agomelatine can be used in sexual dysfunctions, that it possesses properties of ovulation inhibitors, immunomodulators and that it is likely to be used in the treatment of cancers.
  • the crystalline form V of agomelatine will be used preferably in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, disorders appetite and obesity.
  • the invention also extends to pharmaceutical compositions containing as active principle the crystalline form V of the compound of formula (I) with one or more inert, non-toxic and suitable excipients.
  • pharmaceutical compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, single or coated tablets, granules, sublingual tablets, capsules, tablets, suppositories, creams, ointments, skin gels, injectables, oral suspensions and chewables.
  • the useful dosage is adaptable according to the nature and severity of the condition, the route of administration and the age and weight of the patient. This dosage ranges from 0.1 mg to 1 g per day in one or more doses.
  • Example 1 Crystalline form V of N - [2- (7-methoxy-1-naphthyl) ethyl] acetamide
  • Preparation formula for 1000 tablets 25 mg doses: Composed of Example 1 or 2 25 g Lactose monohydrate 62 g Magnesium Stearate 1.3 g Corn starch 26 g maltodextrins 9 g Anhydrous colloidal silica 0.3 g Pregelatinized maize starch type A 4 g Stearic acid 2.6 g
  • Preparation formula for 1000 tablets 25 mg doses: Composed of Example 1 or 2 25 g Lactose monohydrate 62 g Magnesium Stearate 1.3 g povidone 9 g Anhydrous colloidal silica 0.3 g Cellulose sodium glycolate 30 g Stearic acid 2.6 g

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Reproductive Health (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Anesthesiology (AREA)
  • Psychology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pregnancy & Childbirth (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Forme cristalline V du composé de formule (I) :
Figure imga0001
 caractérisée par son diagramme de diffraction X sur poudre.
Médicaments

Description

  • La présente invention concerne une nouvelle forme cristalline V de l'agomélatine ou N-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide de formule (I) :
    Figure imgb0001
     son procédé de préparation ainsi que les compositions pharmaceutiques qui la contiennent.
  • L'agomélatine ou N-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide possède des propriétés pharmacologiques intéressantes.
  • Il présente en effet la double particularité d'être d'une part agoniste sur les récepteurs du système mélatoninergique et d'autre part antagoniste du récepteur 5-HT2C. Ces propriétés lui confère une activité dans le système nerveux central et plus particulièrement dans le traitement de la dépression majeure, des dépressions saisonnières, des troubles du sommeil, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, des troubles de l'appétit et de l'obésité.
  • L'agomélatine, sa préparation et son utilisation en thérapeutique ont été décrits dans le brevet européen EP 0 447 285 .
  • Compte tenu de l'intérêt pharmaceutique de ce composé, il était primordial de l'obtenir avec une excellente pureté, et notamment sous une forme parfaitement reproductible, présentant des caractéristiques intéressantes de dissolution et de facilité de formulation permettant son stockage prolongé sans conditions particulières de température, de lumière, d'humidité ou de taux d'oxygène.
  • Le brevet EP 0 447 285 décrit l'accès en huit étapes à l'agomélatine à partir de la 7-méthoxy-1-tétralone. Cependant, ce document ne précise pas les conditions d'obtention de l'agomélatine sous une forme présentant ces caractéristiques de manière reproductible.
  • La demanderesse a présentement mis au point un procédé d'obtention de l'agomélatine sous une forme cristalline bien définie, parfaitement reproductible et présentant de ce fait des caractéristiques intéressantes de dissolution et de facilité de formulation.
  • Plus spécifiquement, la présente invention concerne la forme cristalline V du composé de formule (I), caractérisée par le diagramme de diffraction X sur poudre suivant, mesuré sur un diffractomètre Siemens D5005 (anticathode de cuivre) et exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta, et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) :
    2-Theta (°) d (Å) Intensité
    exp. exp. (%)
    9,84 8,979 17
    12,40 7,134 15
    13,31 6,646 19
    15,14 5,848 18
    15,98 5,543 18
    16,62 5,329 19
    17,95 4,939 100
    18,88 4,697 65
    20,49 4,332 24
    20,99 4,228 34
    23,07 3,852 39
    23,44 3,792 36
    24,28 3,663 58
    25,10 3,545 19
    26,02 3,422 15
    26,82 3,322 19
    27,51 3,239 16
  • L'invention s'étend également au procédé de préparation de la forme cristalline V du composé de formule (I), caractérisé en ce que l'on soumet l'agomélatine à un broyage mécanique dit « de haute énergie ».
    Dans le procédé de cristallisation selon l'invention, on peut utiliser le composé de formule (I) obtenu par n'importe quel procédé.
  • L'invention s'étend également à un autre procédé de préparation de la forme cristalline V du composé de formule (I), caractérisé en ce que l'on chauffe l'agomélatine jusqu'à fusion complète puis on le place à température ambiante et simultanément on ajoute une très petite quantité de la forme cristalline V du composé de formule (I) fraîchement préparée, puis on laisse ensuite refroidir jusqu'à cristallisation complète.
    De préférence, dans ce second procédé de cristallisation selon l'invention, l'agomélatine sera fondu à 110°C.
    La quantité de forme cristalline V ajoutée dans ce second procédé de cristallisation selon l'invention sera comprise de préférence entre 1/100 et 1/50 du poids d'agomélatine.
    Dans ce second procédé de cristallisation selon l'invention, on peut utiliser le composé de formule (I) obtenu par n'importe quel procédé.
  • L'obtention de cette forme cristalline a pour avantage de permettre la préparation de formulations pharmaceutiques ayant une composition constante et reproductible, présentant des caractéristiques de dissolution particulièrement intéressantes, ce qui est particulièrement avantageux lorsque ces formulations sont destinées à l'administration orale.
  • L'étude pharmacologique de la forme V ainsi obtenue a montré une importante activité sur le système nerveux central ainsi que sur la microcirculation qui permet d'établir son utilité dans le traitement du stress, des troubles du sommeil, de l'anxiété, de la dépression majeure, des dépressions saisonnières, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, de la schizophrénie, des attaques de panique, de la mélancolie, des troubles de l'appétit, de l'obésité, de l'insomnie, de la douleur, des troubles psychotiques, de l'épilepsie, du diabète, de la maladie de Parkinson, de la démence sénile, des divers désordres liés au vieillissement normal ou pathologique, de la migraine, des pertes de mémoire, de la maladie d'Alzheimer, ainsi que dans les troubles de la circulation cérébrale. Dans un autre domaine d'activité, il apparaît que dans le traitement, la forme V de l'agomélatine peut être utilisée dans les dysfonctionnements sexuels, qu'elle possède des propriétés d'inhibiteurs de l'ovulation, d'immunomodulateurs et qu'elle est susceptible d'être utilisée dans le traitement des cancers.
  • La forme cristalline V de l'agomélatine sera utilisée de préférence dans les traitements de la dépression majeure, des dépressions saisonnières, des troubles du sommeil, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, des troubles de l'appétit et de l'obésité.
  • L'invention s'étend aussi aux compositions pharmaceutiques renfermant comme principe actif la forme cristalline V du composé de formule (I) avec un ou plusieurs excipients inertes, non toxiques et appropriés. Parmi les compositions pharmaceutiques selon l'invention, on pourra citer plus particulièrement celles qui conviennent pour l'administration orale, parentérale (intraveineuse ou sous-cutanée), nasale, les comprimés simples ou dragéifiés, les granulés, les comprimés sublinguaux, les gélules, les tablettes, les suppositoires, les crèmes, les pommades, les gels dermiques, les préparations injectables, les suspensions buvables et les pâtes à mâcher.
  • La posologie utile est adaptable selon la nature et la sévérité de l'affection, la voie d'administration ainsi que l'âge et le poids du patient. Cette posologie varie de 0,1 mg à 1 g par jour en une ou plusieurs prises.
  • Les exemples ci-dessous illustrent l'invention, mais ne la limitent en aucune façon.
    • Exemple 1 : Forme cristalline V du N-[2-(7-Méthoxy-1-naphtyl)éthyl]acétamide
  • 100 g de N-[2-(7-Méthoxy-1-naphtyl)éthyl]acétamide sont placés dans le broyeur mécanique de type vario-planetary mill pendant environ 6 heures et le solide obtenu est caractérisé par le diagramme de diffraction X sur poudre suivant, mesuré sur un diffractomètre Siemens D5005 (anticathode de cuivre) et exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta, et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) :
    2-Theta (°) d (Å) Intensité
    exp. exp. (%)
    9,84 8,979 17
    12,40 7,134 15
    13,31 6,646 19
    15,14 5,848 18
    15,98 5,543 18
    16,62 5,329 19
    17,95 4,939 100
    18,88 4,697 65
    20,49 4,332 24
    20,99 4,228 34
    23,07 3,852 39
    23,44 3,792 36
    24,28 3,663 58
    25,10 3,545 19
    26,02 3,422 15
    26,82 3,322 19
    27,51 3,239 16
    • Exempte 2 : Forme cristalline V du N-[2-(7-Méthoxy-1-naphtyl)éthyl]acétamide
  • 4 g de N-[2-(7-Méthoxy-1-naphtyl)éthyl]acétamide sont placés dans une étuve ventilée à 110°C. Après une heure à 110°C, le produit est mis à température ambiante et ensemencé avec 0,05 g de forme cristalline V du N-[2-(7-Méthoxy-1-naphtyl)éthyl]acétamide structuralement pure obtenue par broyage haute énergie. Au bout de 5 minutes, la cristallisation est totale et le solide obtenu est caractérisé par le diagramme de diffraction X sur poudre suivant, mesuré sur un diffractomètre Siemens D5005 (anticathode de cuivre) et exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta, et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) :
    2-Theta (°) d (Å) Intensité
    exp. exp. (%)
    9,84 8,979 17
    12,40 7,134 15
    13,31 6,646 19
    15,14 5,848 18
    15,98 5,543 18
    16,62 5,329 19
    17,95 4,939 100
    18,88 4,697 65
    20,49 4,332 24
    20,99 4,228 34
    23,07 3,852 39
    23,44 3,792 36
    24,28 3,663 58
    25,10 3,545 19
    26,02 3,422 15
    26,82 3,322 19
    27,51 3,239 16
    • Exemple 3 : Composition pharmaceutique
  • Formule de préparation pour 1000 comprimés doses à 25 mg :
    Composé de l'Exemple 1 ou 2 25 g
    Lactose monohydrate 62 g
    Stéarate de Magnésium 1,3 g
    Amidon de maïs 26 g
    Maltodextrines 9 g
    Silice colloïdale anhydre 0,3 g
    Amidon de maïs prégélatinisé type A 4 g
    Acide stéarique 2,6 g
    • Exemple 4 : Composition pharmaceutique
  • Formule de préparation pour 1000 comprimés doses à 25 mg :
    Composé de l'Exemple 1 ou 2 25 g
    Lactose monohydrate 62 g
    Stéarate de Magnésium 1,3 g
    Povidone 9 g
    Silice colloïdale anhydre 0,3 g
    Cellulose sodium glycolate 30 g
    Acide stéarique 2,6 g

Claims (6)

  1. Forme cristalline V de l'agomélatine de formule (I) :
    Figure imgb0002
     caractérisée par le diagramme de diffraction X sur poudre suivant, mesuré sur un diffractomètre Siemens D5005 (anticathode de cuivre) et exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta, et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) : 2-Theta (°) d (Å) Intensité exp. exp. (%) 9,84 8,979 17 12,40 7,134 15 13,31 6,646 19 15,14 5,848 18 15,98 5,543 18 16,62 5,329 19 17,95 4,939 100 18,88 4,697 65 20,49 4,332 24 20,99 4,228 34 23,07 3,852 39 23,44 3,792 36 24,28 3,663 58 25,10 3,545 19 26,02 3,422 15 26,82 3,322 19 27,51 3,239 16
  2. Procédé de préparation de la forme cristalline V du composé de formule (I) selon la revendication 1, caractérisé en ce que l'on l'on soumet l'agomélatine à un broyage mécanique dit « de haute énergie ».
  3. Procédé de préparation de la forme cristalline V du composé de formule (I) selon la revendication 1, caractérisé en ce que l'on l'on chauffe l'agomélatine jusqu'à fusion complète puis on le place à température ambiante et simultanément on ajoute une très petite quantité de la forme cristalline V du composé de formule (I) fraîchement préparée, puis on laisse ensuite refroidir jusqu'à cristallisation complète.
  4. Compositions pharmaceutiques contenant comme principe actif la forme cristalline V de l'agomélatine selon la revendication 1, en combinaison avec un ou plusieurs véhicules inertes, non toxiques et pharmaceutiquement acceptables.
  5. Compositions pharmaceutiques selon la revendication 4 utiles pour la fabrication de médicaments pour traiter les troubles du système mélatoninergique.
  6. Compositions pharmaceutiques selon la revendication 4 utiles pour la fabrication de médicaments pour le traitement des troubles du sommeil, du stress, de l'anxiété, des dépressions saisonnières ou de la dépression majeure, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, de la schizophrénie, des attaques de paniques, de la mélancolie, des troubles de l'appétit, de l'obésité, de l'insomnie, des troubles psychotiques, de l'épilepsie, du diabète, de la maladie de Parkinson, de la démence sénile, des divers désordres liés au vieillissement normal ou pathologique, de la migraine, des pertes de mémoire, de la maladie d'Alzheimer, des troubles de la circulation cérébrale, ainsi que dans les dysfonctionnements sexuels, en tant qu'inhibiteurs de l'ovulation, d'immunomodulateurs et dans le traitement des cancers.
EP06291251A 2005-08-03 2006-08-02 Nouvelle forme cristalline V de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent Active EP1752443B1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MEP-2012-327A ME02026B (fr) 2005-08-03 2006-08-02 Nouvelle forme cristalline V de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
EP10011469A EP2277857A3 (fr) 2005-08-03 2006-08-02 Nouvelle forme cristalline V de l'agomélatine, son procédé de préparation et les compositions pharmaceutiques qui la contiennent
SI200631396T SI1752443T1 (sl) 2005-08-03 2006-08-02 Nova kristalinična oblika V agomelatina, postopek za njeno pripravo in farmacevtski sestavki, ki jo vsebujejo
PL06291251T PL1752443T3 (pl) 2005-08-03 2006-08-02 Nowa postać krystaliczna V agomelatyny, sposób jej wytwarzania i kompozycje farmaceutyczne, które ją zawierają
CY20121100635T CY1113011T1 (el) 2005-08-03 2012-07-18 Νεα κρυσταλλικη μορφη v της αγομελατινης, μεθοδος παρασκευης αυτης και φαρμακευτικες συνθεσεις που περιεχουν αυτην

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR0508278A FR2889523B1 (fr) 2005-08-03 2005-08-03 Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP10011469.3 Division-Into 2010-09-29

Publications (2)

Publication Number Publication Date
EP1752443A1 true EP1752443A1 (fr) 2007-02-14
EP1752443B1 EP1752443B1 (fr) 2012-07-11

Family

ID=36581629

Family Applications (2)

Application Number Title Priority Date Filing Date
EP10011469A Withdrawn EP2277857A3 (fr) 2005-08-03 2006-08-02 Nouvelle forme cristalline V de l'agomélatine, son procédé de préparation et les compositions pharmaceutiques qui la contiennent
EP06291251A Active EP1752443B1 (fr) 2005-08-03 2006-08-02 Nouvelle forme cristalline V de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP10011469A Withdrawn EP2277857A3 (fr) 2005-08-03 2006-08-02 Nouvelle forme cristalline V de l'agomélatine, son procédé de préparation et les compositions pharmaceutiques qui la contiennent

Country Status (37)

Country Link
EP (2) EP2277857A3 (fr)
JP (1) JP4575337B2 (fr)
CN (1) CN100448843C (fr)
AP (1) AP2486A (fr)
AR (1) AR057715A1 (fr)
AU (1) AU2006203342B2 (fr)
BR (1) BRPI0603059A (fr)
CA (1) CA2555115C (fr)
CR (1) CR8529A (fr)
CU (1) CU20060153A7 (fr)
CY (1) CY1113011T1 (fr)
DK (1) DK1752443T3 (fr)
EA (1) EA011030B1 (fr)
EC (1) ECSP066715A (fr)
ES (1) ES2391406T3 (fr)
FR (1) FR2889523B1 (fr)
GT (1) GT200600346A (fr)
HR (1) HRP20120779T1 (fr)
IL (1) IL177173A (fr)
JO (1) JO2793B1 (fr)
MA (1) MA28451B1 (fr)
ME (1) ME02026B (fr)
MX (1) MXPA06008789A (fr)
MY (1) MY139902A (fr)
NO (1) NO336967B1 (fr)
NZ (1) NZ548864A (fr)
PE (1) PE20070365A1 (fr)
PL (1) PL1752443T3 (fr)
PT (1) PT1752443E (fr)
RS (1) RS52423B (fr)
SA (1) SA06270255B1 (fr)
SG (1) SG130110A1 (fr)
SI (1) SI1752443T1 (fr)
TW (1) TWI359128B (fr)
UA (1) UA83720C2 (fr)
WO (1) WO2007015004A2 (fr)
ZA (1) ZA200606453B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2151430A1 (fr) * 2008-08-05 2010-02-10 Les Laboratoires Servier Nouveau procédé d'obtention de la forme cristalline V de l'agomélatine
WO2013082302A1 (fr) 2011-11-30 2013-06-06 Ratiopharm Gmbh Complexe agomélatine-urée et formes cristallines de celui-ci
WO2014096373A1 (fr) 2012-12-21 2014-06-26 Laboratorios Lesvi, S. L. Procédé de préparation de n-(2-(7-méthoxy-1-naphtalényl)éthyl)acétamide et de formes solides de celui-ci

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101481321B (zh) * 2009-02-27 2012-04-18 上海医药工业研究院 阿戈美拉汀卤化氢复合物及其制备方法
CN101585779B (zh) * 2009-03-10 2014-04-02 上海医药工业研究院 阿戈美拉汀的晶型vi及其制备方法和应用
WO2011006387A1 (fr) * 2009-07-11 2011-01-20 浙江华海药业股份有限公司 Procédé pour la préparation d'agomélatine, cristaux d'agomélatine et leur procédé de préparation
CN102001959B (zh) * 2009-09-01 2014-07-02 北京本草天源药物研究院 一种药物晶体及其制备方法和用途
CN102050755B (zh) * 2009-10-29 2014-11-05 重庆医药工业研究院有限责任公司 阿戈美拉汀的晶型及其制备方法
CN101781226B (zh) 2009-12-23 2012-03-28 天津泰普药品科技发展有限公司 阿戈美拉汀及其药物组合物
EP2580183B1 (fr) 2010-06-10 2014-07-23 Gador S.A. Nouveau procédé de préparation de n-[2-(7-méthoxy-1-naphtyl)-éthyl]acétamide
CN102000583B (zh) * 2010-11-18 2012-08-15 烟台万华聚氨酯股份有限公司 一种氯化氢氧化制氯气的催化剂及其制备方法
CN102690209A (zh) * 2011-03-23 2012-09-26 上海医药工业研究院 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
CN102690210A (zh) * 2011-03-23 2012-09-26 上海医药工业研究院 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
BR112013030973B1 (pt) * 2011-06-02 2021-08-10 CHINOIN Zrt. Processo para a preparação de amidas de prostaglandina
FR2978916B1 (fr) 2011-08-10 2013-07-26 Servier Lab Composition pharmaceutique solide pour administration buccale d'agomelatine
CZ2012108A3 (en) 2012-02-15 2013-02-27 Zentiva Ks A method for the manufacture of a polymorphously stable pharmaceutical composition containing agomelatine
CN103360275B (zh) * 2012-03-30 2015-04-22 上海创诺制药有限公司 一种制备阿戈美拉汀ⅰ型晶体的方法
FR3001894A1 (fr) 2013-02-08 2014-08-15 Servier Lab Composition pharmaceutique solide pour administration buccale d'agomelatine
ES2645223T3 (es) 2013-06-06 2017-12-04 Zentiva, K.S. Formulaciones de agomelatina que comprenden agomelatina en forma de co-cristales
EP2810647A1 (fr) 2013-06-06 2014-12-10 Zentiva, a.s. Formulations pharmaceutiques, comprenant l'agomélatine sous forme d'un co-cristal de l'agomélatine avec un acide organique
CZ2013621A3 (cs) 2013-08-13 2015-02-25 Zentiva, K.S. Termodynamicky stabilní tuhý roztok agomelatinu pro použití ve farmaceutické formulaci
WO2015124496A1 (fr) 2014-02-19 2015-08-27 Synthon B.V. Composition pharmaceutique comprenant de l'agomélatine amorphe
FR3033131B1 (fr) 2015-02-26 2017-11-17 Servitronique Glissiere pour ses systemes de reglage coulissants et procede d'assemblage
EP3075724B1 (fr) 2015-03-31 2023-07-12 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Forme solide de l'agomélatine
EP3466413A1 (fr) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Composition pharmaceutique contenant de l'agomelatine et son procédé de préparation
EP3466923A1 (fr) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Procédés de préparation d'agomélatine dans une forme cristalline
CN113952323A (zh) * 2021-12-10 2022-01-21 李甜 阿戈美拉汀在抑制Ube2c蛋白表达中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP1564202A1 (fr) * 2004-02-13 2005-08-17 Les Laboratoires Servier Nouveau procédé de synthèse et nouvelle forme cristalline de l'agomelatine ainsi que les compositions pharmaceutiques qui la contiennent

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2866336B1 (fr) * 2004-02-13 2006-03-24 Servier Lab Nouveau procede de synthese du (7-methoxy-3,4-dihydro-1-naphtalenyl) acetonitrile et application a la synthese de l'agomelatine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP1564202A1 (fr) * 2004-02-13 2005-08-17 Les Laboratoires Servier Nouveau procédé de synthèse et nouvelle forme cristalline de l'agomelatine ainsi que les compositions pharmaceutiques qui la contiennent

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHILMAN-BLAIR K ET AL: "AGOMELATINE. ANTIDEPRESSANT TREATMENT OF BIPOLAR DISORDER MELATONIN AGONUST/5-HT20 ANTAGONIST", DRUGS OF THE FUTURE, BARCELONA, ES, vol. 28, no. 1, January 2003 (2003-01-01), pages 7 - 13, XP009036058, ISSN: 0377-8282 *
DEPREUX P ET AL: "SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF NOVEL NAPHTHALENIC AND BIOISOSTERIC AMIDIC DERIVATIVES AS MELATONIN RECEPTOR LIGANDS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 20, 30 September 1994 (1994-09-30), pages 3231 - 3239, XP002016146, ISSN: 0022-2623 *
TINANT B ET AL: "N-[2-(7-METHOXY-1-NAPHTHYL)ETHYL]ACETAMIDE, A POTENT MELATONIN ANALOG", ACTA CRYSTALLOGRAPHICA SECTION C. CRYSTAL STRUCTURE COMMUNICATIONS, MUNKSGAARD, COPENHAGEN, DK, vol. C50, no. 6, 1994, pages 907 - 910, XP009047983, ISSN: 0108-2701 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2151430A1 (fr) * 2008-08-05 2010-02-10 Les Laboratoires Servier Nouveau procédé d'obtention de la forme cristalline V de l'agomélatine
WO2010015747A1 (fr) * 2008-08-05 2010-02-11 Les Laboratoires Servier Nouveau procede d'obtention de la forme cristalline v de l'agomelatine
FR2934856A1 (fr) * 2008-08-05 2010-02-12 Servier Lab Nouveau procede d'obtention de la forme cristalline v de l'agomelatine
US8252957B2 (en) 2008-08-05 2012-08-28 Les Laboratoires Servier Process for obtaining the crystalline form V of agomelatine
WO2013082302A1 (fr) 2011-11-30 2013-06-06 Ratiopharm Gmbh Complexe agomélatine-urée et formes cristallines de celui-ci
WO2014096373A1 (fr) 2012-12-21 2014-06-26 Laboratorios Lesvi, S. L. Procédé de préparation de n-(2-(7-méthoxy-1-naphtalényl)éthyl)acétamide et de formes solides de celui-ci

Also Published As

Publication number Publication date
IL177173A0 (en) 2006-12-10
NO20063517L (no) 2007-02-05
PE20070365A1 (es) 2007-06-02
BRPI0603059A (pt) 2007-08-14
TWI359128B (en) 2012-03-01
CU20060153A7 (es) 2012-04-15
TW200736199A (en) 2007-10-01
WO2007015004A3 (fr) 2007-03-22
EP2277857A3 (fr) 2011-06-01
RS52423B (sr) 2013-02-28
CA2555115C (fr) 2013-12-10
ZA200606453B (en) 2007-12-27
HRP20120779T1 (hr) 2012-10-31
IL177173A (en) 2011-10-31
MXPA06008789A (es) 2007-02-02
EA011030B1 (ru) 2008-12-30
NO336967B1 (no) 2015-12-07
CR8529A (es) 2006-12-07
CY1113011T1 (el) 2016-04-13
ES2391406T3 (es) 2012-11-26
AR057715A1 (es) 2007-12-12
FR2889523B1 (fr) 2007-12-28
MY139902A (en) 2009-11-30
AP2006003695A0 (en) 2006-08-31
CN1907958A (zh) 2007-02-07
EA200601273A1 (ru) 2007-02-27
JO2793B1 (en) 2014-03-15
CN100448843C (zh) 2009-01-07
WO2007015004A2 (fr) 2007-02-08
EP1752443B1 (fr) 2012-07-11
SI1752443T1 (sl) 2012-10-30
FR2889523A1 (fr) 2007-02-09
CA2555115A1 (fr) 2007-02-03
MA28451B1 (fr) 2007-03-01
AU2006203342A1 (en) 2007-02-22
HK1098128A1 (zh) 2007-07-13
JP2007056017A (ja) 2007-03-08
DK1752443T3 (da) 2012-10-22
SG130110A1 (en) 2007-03-20
ME02026B (fr) 2012-11-06
UA83720C2 (ru) 2008-08-11
JP4575337B2 (ja) 2010-11-04
NZ548864A (en) 2008-03-28
PL1752443T3 (pl) 2012-11-30
AU2006203342B2 (en) 2012-07-19
PT1752443E (pt) 2012-07-25
EP2277857A2 (fr) 2011-01-26
SA06270255B1 (ar) 2010-06-13
GT200600346A (es) 2007-02-28
ECSP066715A (fr) 2007-03-29
AP2486A (en) 2012-10-03

Similar Documents

Publication Publication Date Title
EP1752443B1 (fr) Nouvelle forme cristalline V de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
EP2058296B1 (fr) Nouvelle forme cristalline VI de l'agomélatine, son procédé de préparation et les compositions pharmaceutiques qui la contiennent
EP2210872B1 (fr) Nouvelle forme cristalline iii de l'agomélatine, son procédé de préparation et les compositions pharmaceutiques qui la contiennent
WO2007015002A2 (fr) Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
EP2532647B1 (fr) Nouveaux co-cristaux d'agomelatin.
US20060270877A1 (en) Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it
KR100904116B1 (ko) 아고멜라틴의 ⅴ 결정형, 이의 제조 방법 및 이를 함유하는 약제 조성물
KR20070017020A (ko) 아고멜라틴의 결정질 형태 ⅳ, 이의 제조 방법 및 이를함유하는 약제 조성물
KR20070017019A (ko) 아고멜라틴의 결정질 형태 ⅲ, 이의 제조 방법 및 이를함유하는 약제 조성물

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060810

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

17Q First examination report despatched

Effective date: 20070903

AKX Designation fees paid

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AXX Extension fees paid

Extension state: YU

Payment date: 20060810

Extension state: MK

Payment date: 20060810

Extension state: HR

Payment date: 20060810

Extension state: BA

Payment date: 20060810

Extension state: AL

Payment date: 20060810

RAX Requested extension states of the european patent have changed

Extension state: RS

Payment date: 20060810

Extension state: MK

Payment date: 20060810

Extension state: HR

Payment date: 20060810

Extension state: BA

Payment date: 20060810

Extension state: AL

Payment date: 20060810

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: BOHEST AG

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 566058

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120715

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20120719

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: FRENCH

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602006030656

Country of ref document: DE

Effective date: 20120906

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: LES LABORATOIRES SERVIER

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20120779

Country of ref document: HR

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E006924

Country of ref document: EE

Effective date: 20120802

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20120401581

Country of ref document: GR

Effective date: 20120903

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20120779

Country of ref document: HR

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2391406

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20121126

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 12679

Country of ref document: SK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20130412

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E015627

Country of ref document: HU

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602006030656

Country of ref document: DE

Effective date: 20130412

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: HOLBEINSTRASSE 36-38, 4051 BASEL (CH)

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 13

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20120779

Country of ref document: HR

Payment date: 20190619

Year of fee payment: 14

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20120779

Country of ref document: HR

Payment date: 20200703

Year of fee payment: 15

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20120779

Country of ref document: HR

Payment date: 20210629

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20220621

Year of fee payment: 17

Ref country code: LT

Payment date: 20220621

Year of fee payment: 17

Ref country code: GB

Payment date: 20220630

Year of fee payment: 17

Ref country code: EE

Payment date: 20220621

Year of fee payment: 17

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20120779

Country of ref document: HR

Payment date: 20220629

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20220624

Year of fee payment: 17

Ref country code: LV

Payment date: 20220621

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20220727

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SK

Payment date: 20220704

Year of fee payment: 17

Ref country code: SE

Payment date: 20220714

Year of fee payment: 17

Ref country code: RO

Payment date: 20220727

Year of fee payment: 17

Ref country code: LU

Payment date: 20220809

Year of fee payment: 17

Ref country code: IT

Payment date: 20220822

Year of fee payment: 17

Ref country code: IE

Payment date: 20220819

Year of fee payment: 17

Ref country code: FI

Payment date: 20220708

Year of fee payment: 17

Ref country code: ES

Payment date: 20220905

Year of fee payment: 17

Ref country code: DK

Payment date: 20220809

Year of fee payment: 17

Ref country code: DE

Payment date: 20220630

Year of fee payment: 17

Ref country code: CZ

Payment date: 20220701

Year of fee payment: 17

Ref country code: BG

Payment date: 20220803

Year of fee payment: 17

Ref country code: AT

Payment date: 20220721

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SI

Payment date: 20220712

Year of fee payment: 17

Ref country code: MC

Payment date: 20220801

Year of fee payment: 17

Ref country code: IS

Payment date: 20220705

Year of fee payment: 17

Ref country code: HU

Payment date: 20220625

Year of fee payment: 17

Ref country code: GR

Payment date: 20220829

Year of fee payment: 17

Ref country code: FR

Payment date: 20220823

Year of fee payment: 17

Ref country code: BE

Payment date: 20220824

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20220823

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20220728

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20220628

Year of fee payment: 17

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20120779

Country of ref document: HR

Effective date: 20230802

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20230802

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602006030656

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 12679

Country of ref document: SK

Effective date: 20230802

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E006924

Country of ref document: EE

Effective date: 20230831

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20230831

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20230901

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240307

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 566058

Country of ref document: AT

Kind code of ref document: T

Effective date: 20230802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20230802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230803

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240307

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240229

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240202

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230803

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20230831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230901

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230803

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230803

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230901

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20240507

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20240927

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230803

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230802

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230803

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240305